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Molecular and Cellular Biology

Xichuan Li, Zhenzhen Lin, Hao Wang, Dan Zhao, Xing Xu, Yiliang Wei, Xiaoting Li, Xiaobo Li, Yougui Xiang, Lance S Terada, Zhe Liu
Half of the genes in the human genome contain alternative promoters, some of which generate products with opposing functions. Aberrant silencing or activation of such alternative promoters is associated with multiple diseases including cancer, but little is known regarding the molecular mechanisms that control alternative promoter choice. The SHC1 gene encodes p46Shc/p52Shcand p66Shc, proteins oppositely regulating anchorage independent growth that are produced respectively by transcription initiated from the upstream and downstream tandem promoters of SHC1 Here we demonstrate that activation of these promoters is mutually exclusive on separate alleles in single primary endothelial cells in a heritable fashion, assuring expression of both transcripts by the cell...
February 12, 2018: Molecular and Cellular Biology
Marina Pascual-Ortiz, Adolfo Saiardi, Eva Walla, Visnja Jakopec, Natascha A Künzel, Ingrid Span, Anand Vangala, Ursula Fleig
The generation of two daughter cells with the same genetic information requires error-free chromosome segregation during mitosis. Chromosome transmission fidelity is dependent on spindle structure/function which requires Asp1 in the fission yeast Schizosaccharomyces pombe. Asp1 belongs to the PPIP5Ks/Vip1 family which generates high energy inositol pyrophosphate (IPP) molecules. Here we show that Asp1 is a bi-functional enzyme in vivo : Asp1 kinase generates specific IPPs which are the substrates of the Asp1 pyrophosphatase...
February 12, 2018: Molecular and Cellular Biology
Jungki Min, Lalith Perera, Juno M Krahn, Christine M Jewell, Andrea F Moon, John A Cidlowski, Lars C Pedersen
Glucocorticoid receptor β (GRβ) is associated with glucocorticoid resistance via dominant negative regulation of GRα. To better understand how GRβ functions as a dominant negative inhibitor of GRα at a molecular level, we determined the crystal structure of the ligand binding domain of GRβ complexed with antagonist RU-486. The structure reveals that RU-486 binds in the same ligand binding pocket as in GRα and the unique C-terminal amino acids of GRβ are mostly disordered. Binding energy analysis suggests that these C-terminal residues of GRβ do not contribute to RU-486 binding...
February 5, 2018: Molecular and Cellular Biology
Megumi C Katoh, Yunshin Jung, Chioma M Ugbama, Miki Shimbo, Akihiro Kuno, Walaa A Basha, Takashi Kudo, Hisashi Oishi, Satoru Takahashi
The MafB transcription factor is expressed in pancreatic α- and β-cells during development but becomes exclusive to α-cells in adult rodents. Mafb-null (Mafb-/- ) mice were reported to reduce α- and β-cell numbers throughout embryonic development. To further analyze postnatal function of MafB in the pancreas, we generated endocrine cell-specific (MafbΔEndo ) and tamoxifen-dependent (MafbΔTAM ) Mafb knockout mice. MafbΔEndo mice exhibited reduced population of insulin+ and glucagon+ cells at postnatal day 0 but recovered the insulin+ cell population by 8 weeks of age...
January 29, 2018: Molecular and Cellular Biology
Qiong L Zhou, Ye Song, Chun-Hong Huang, Jun-Yuan Huang, Zhenwei Gong, Zhangping Liao, Andria G Sharma, Lily Greene, Justin Z Deng, Michael C Rigor, Xiangyang Xie, Songtao Qi, Julio E Ayala, Zhen Y Jiang
CDP138 is a calcium- and lipid-binding protein that is involved in membrane trafficking. Here we report mice without CDP138 develop obesity under normal chow diet (NCD) or high-fat diet (HFD) conditions. CDP138-/- mice have lower energy expenditure, oxygen consumption and body temperature in comparison with wild-type (WT) mice. CDP138 is exclusively expressed in adrenal medulla and is co-localized with tyrosine hydroxylase (TH), a marker of sympathetic nervous terminals, in the inguinal fat. In comparison with WT controls, CDP138-/- mice had altered catecholamine levels in the circulation, adrenal grand, and inguinal fat...
January 29, 2018: Molecular and Cellular Biology
Aaron C Baldwin, Aaron Naatz, Richard N Bohnsack, Jacob T Bartosiak, Bryndon J Oleson, Polly A Hansen, Nancy M Dahms, John A Corbett
Palmitate attenuates insulin secretion and reduces the viability of insulin producing cells. Previous studies have identified the aberrant or mis-palmitoylation of proteins as one mechanism by which palmitate causes β-cell damage. In this report we identify a role for lysosomal protein degradation as a mechanism by which β-cells defend themselves against excess palmitate. The cation-independent mannose 6-phosphate receptor (CI-MPR) is responsible for the trafficking of mannose 6-phosphate tagged proteins to lysosomes via Golgi sorting and from extracellular locations through endocytosis...
January 29, 2018: Molecular and Cellular Biology
Joonyoung Her, Chandni Ray, Jake Altshuler, Haiyan Zhang, Samuel F Bunting
Complete replication of the genome is an essential prerequisite for normal cell division, but a variety of factors can block the replisome, triggering 'replication stress' and potentially causing mutation or cell death. The cellular response to replication stress involves recruitment of proteins to stabilize the replication fork and transmit a stress signal to pause the cell cycle and allow fork restart. We find that the ubiquitously-expressed DNA damage response factor, 53BP1, is required for the normal response to replication stress...
January 29, 2018: Molecular and Cellular Biology
Yuhan Bi, Xiongjie Shi, Junjie Zhu, Xiudong Guan, Wojciech G Garbacz, Yixian Huang, Li Gao, Jiong Yan, Meishu Xu, Songrong Ren, Shunlin Ren, Yulan Liu, Xiaochao Ma, Song Li, Wen Xie
The cholesterol sulfotransferase SULT2B1b converses cholesterol to cholesterol sulfate (CS). We previously reported that SULT2B1b inhibits hepatic gluconeogenesis by antagonizing the gluconeogenic activity of hepatocyte nuclear factor 4α (HNF4α). In this study, we showed that the SULT2B1b gene is a transcriptional target of HNF4α, which led to our hypothesis that the induction of SULT2B1b by HNF4α represents a negative feedback to limit the gluconeogenic activity of HNF4α. Indeed, down-regulation of Sult2B1b enhanced the gluconeogenic activity of HNF4α, which may have been accounted for by the increased acetylation of HNF4α as a result of decreased expression of the HNF4α deacetylase Sirt1...
January 29, 2018: Molecular and Cellular Biology
Renata Collard, Tomas Majtan, Insun Park, Jan P Kraus
Propionic acidemia is caused by a deficiency of the enzyme propionyl-CoA carboxylase (PCC) located in the mitochondrial matrix. Cell-penetrating peptides, including TAT, offer a potential to deliver a cargo into the mitochondrion. Here, we investigated the delivery of an α6β6 PCC enzyme into mitochondria using HIV transactivator of transcription (TAT) peptide at several levels: into isolated mitochondria, patient fibroblast cells and a mouse model. Western blotting of mitochondria as well as enzyme activity confirmed the import of a fusion TAT-PCC into mitochondria as well as into patient cells and the mitochondrial localization was confirmed additionally by confocal imaging...
January 29, 2018: Molecular and Cellular Biology
Muniesh Muthaiyan Shanmugam, Prerana Bhan, Hsin-Yi Huang, Jung Hsieh, Tzu-En Hua, Gong-Her Wu, Helly Punjabi, Víctor Daniel Lee Aplícano, Chih-Wei Chen, Oliver Ingvar Wagner
To understand how ciliopathies such as polycystic kidney disease or Bardet-Biedl syndrome develop, we need to understand the basic molecular mechanisms underlying cilia development. Cilia growth depends on a functional intraflagellar transport (IFT) machinery, and we hypothesized that various kinases and phosphatases might be involved in this regulatory process. A candidate screen revealed two kinases PKG-1 (a cGMP-dependent protein kinase) and GCK-2 (a MAP4K3 kinase involved in mTOR signaling) significantly affecting dye filling, chemotaxis, cilia morphology, and IFT component distribution...
January 29, 2018: Molecular and Cellular Biology
Qian Li, Yue Hua, Yilin Yang, Xinyu He, Wei Zhu, Jiyong Wang, Xiaoqing Gan
Osteocalcin has recently been shown to regulate energy homeostasis through multiple pathways. Adipose tissue is a main organ of energy metabolism, and administration of recombinant osteocalcin in mice promoted energy consumption, thus counteracting obesity and glucose intolerance. The regulation of osteocalcin in islet β cells has been well documented; however, it is unknown whether osteocalcin can also act on adipocytes, and if does, how it functions. Here, we provided evidence to demonstrate a specific role for osteocalcin in brown adipocyte thermogenesis...
January 22, 2018: Molecular and Cellular Biology
Aki Ushiki, Hitomi Matsuzaki, Akiyoshi Fukamizu, Keiji Tanimoto
The renin-angiotensin system plays an essential role in blood pressure homeostasis. Because renin activity is reflected as a blood pressure phenotype, its gene expression in the kidney is tightly regulated by a feedback mechanism, i.e. renin gene transcription is suppressed in a hypertensive state. To address the molecular mechanisms controlling hypertension-responsive mouse renin (mRen) gene regulation, we deleted either 5' (17 kb) or 3' (78 kb) regions of the endogenous mRen gene and placed the animals in a hypertensive environment...
January 22, 2018: Molecular and Cellular Biology
Shun Kageyama, Tetsuya Saito, Miki Obata, Ryo-Hei Koide, Yoshinobu Ichimura, Masaaki Komatsu
A key anti-oxidant pathway, the Keap1-Nrf2 system, is regulated by p62/Sqstm1 via multiple mechanisms, including gene expression, post-translational modifications such as ubiquitination and phosphorylation, and autophagic degradation of p62/Sqstm1 and Keap1. Herein, we demonstrate a novel mode of regulation of the Keap1-Nrf2 system, mediated by a splicing variant of p62/Sqstm1 pre-mRNA. Ensembl database search and subsequent biochemical analyses in mice revealed the presence of an mRNA that encodes p62/Sqstm1 protein lacking the Keap1-interacting region (KIR), which is essential for the interaction with Keap1...
January 16, 2018: Molecular and Cellular Biology
Dharmendra Kumar Singh, Raj K Pandita, Mayank Singh, Sharmistha Chakraborty, Shashank Hambarde, Deepti Ramnarain, Vijaya Charaka, Kazi Mokim Ahmed, Clayton R Hunt, Tej K Pandita
The hMOF protein belongs to the MYST family of histone acetyltransferases and plays a critical role in transcription and the DNA damage response. MOF is essential for cell proliferation, however its role during replication and replicative stress is unknown. Here we demonstrate that cells depleted for MOF and under replicative stress induced by cisplatin, hydroxyurea or camptothecin have reduced survival, a higher frequency of S-phase specific chromosome damage and increased R-loop formation. MOF depletion decreased replication fork speed and, when combined with replicative stress, also increased stalled replication forks as well as new origin firing...
January 3, 2018: Molecular and Cellular Biology
Xiaorong Wu, Xiuxiang An, Caiguo Zhang, Mingxia Huang
A tightly controlled cellular deoxyribonucleotide (dNTP) pool is critical for maintenance of genome integrity. One mode of dNTP pool regulation is through subcellular localization of ribonucleotide reductase (RNR), the enzyme that catalyzes the rate-limiting step of dNTP biosynthesis. In Saccharomyces cerevisiae, the RNR small subunit Rnr2-Rnr4 is localized to the nucleus, whereas the large subunit Rnr1 is cytoplasmic. As cells enter S phase or encounter DNA damage, Rnr2-Rnr4 relocalizes to the cytoplasm to form an active holoenzyme complex with Rnr1...
December 20, 2017: Molecular and Cellular Biology
Christopher Abdullah, Hasan Korkaya, Shinji Iizuka, Sara A Courtneidge
The transcription factor MYC is important in breast cancer and its mRNA is maintained at a high level even in the absence of gene amplification. The mechanism(s) underlying increased MYC mRNA expression are unknown. Here we demonstrate that MYC mRNA was stabilized upon estrogen stimulation of estrogen receptor-positive breast cancer cells, via SRC-dependent effects on a recently described RNA-binding protein ΔN-IMP1. We also show that loss of the tumor suppressor p53 increased MYC mRNA levels, even in the absence of estrogen stimulation...
December 20, 2017: Molecular and Cellular Biology
Ray M Joe, Anabel Flores, Michael E Doche, Joel M Cline, Erik S Clutter, Paul B Vander, Heimo Riedel, Lawrence S Argetsinger, Christin Carter-Su
The scaffold protein SH2B1, a major regulator of body weight, is recruited to the receptors of multiple cytokines and growth factors, including nerve growth factor (NGF). The β isoform, but not the α isoform, of SH2B1 greatly enhances NGF-dependent neurite outgrowth of PC12 cells. Here we asked how the unique C-terminal tails of the α and β isoforms modulate SH2B1 function. We compared the actions of SH2B1α and SH2B1β to those of the N-terminal 631 amino acids shared by both isoforms. In contrast to the β-tail, the α-tail inhibited the ability of SH2B1 to both cycle through the nucleus and enhance NGF-mediated neurite outgrowth, gene expression, phosphorylation of Akt and PLCγ and autophosphorylation of the NGF receptor TrkA...
December 11, 2017: Molecular and Cellular Biology
Dibesh Thapa, Charlie Nichols, Rekha Bassi, Eva Denise Martin, Shawari Verma, Maria R Conte, Vittorio De Santis, Gian F De Nicola, Michael S Marber
p38α mitogen-activated protein kinase is essential to cellular homeostasis. Two principal mechanisms exist to activate p38α. The first, relies on dedicated dual specificity kinases such as MAP2K3 (MKK3) or MAP2K6 (MKK6), which activate p38α by phosphorylating Thr180 and Tyr182 within the activation segment. The second, is by autophosphorylation of Thr180 and Tyr182 in cis; mediated by p38α binding the scaffold protein TAB1. The second mechanism occurs during myocardial ischemia, where it aggravates myocardial infarction...
December 11, 2017: Molecular and Cellular Biology
Gun-Dong Kim, Riku Das, Xiaoquan Rao, Jixin Zhong, Jeffrey A Deiuliis, Diana L Ramirez-Bergeron, Sanjay Rajagopalan, Ganapati H Mahabeleshwar
Macrophages are strategically distributed in mammalian tissues and play an essential role in priming immune response. However, macrophages need to constantly strike a balance between activation and inhibition state to avoid a futile inflammatory reaction. Herein, we identify the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) as a potent repressor of macrophage pro-inflammatory activation. Gain- and loss-of-function studies revealed that CITED2 is required for optimal peroxisome proliferator-activated receptor gamma (PPARγ) activation and attendant select anti-inflammatory gene expression in macrophages...
December 4, 2017: Molecular and Cellular Biology
Piotr Grabarczyk, Passorn Winkler, Martin Delin, Praveen K Sappa, Sander Bekeschus, Petra Hildebrandt, Grzegorz K Przybylski, Uwe Völker, Elke Hammer, Christian A Schmidt
The BCL11B gene encodes a Krüppel-like, sequence-specific zinc finger transcription factor that acts as either a repressor or an activator, depending on its post-translational modifications. The importance of BCL11B in numerous biological processes in multiple organs has been well established in mouse knockout models. The phenotype of the first de novo monoallelic germline missense mutation in the BCL11B gene (N441K) strongly implies that the mutant protein acts in a dominant negative manner by neutralizing the unaffected protein through the formation of a nonfunctional dimer...
December 4, 2017: Molecular and Cellular Biology
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